Ionizable drug delivery systems for efficient and selective gene therapy

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function.However,a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells.To be excited,the development of ionizable drug delivery systems(IDDSs)has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019(COVID-19)in 2021.Compared with conventional cationic gene vectors,IDDSs can decrease the toxicity of carriers to cell membranes,and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures.Despite the progress,there remain necessary requirements for designing more efficient IDDSs for precise gene therapy.Herein,we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms.The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of plasmid DNA(pDNA)and four kinds of RNA.In particular,organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity.We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future,and indicate ideas for developing next generation gene vectors.

Mesenchymal stem cells-based drug delivery systems for diabetic foot ulcer:A review

The complication of diabetes,which is known as diabetic foot ulcer(DFU),is a significant concern due to its association with high rates of disability and mortality.It not only severely affects patients’quality of life,but also imposes a substantial burden on the healthcare system.In spite of efforts made in clinical practice,treating DFU remains a challenging task.While mesenchymal stem cell(MSC)therapy has been extensively studied in treating DFU,the current efficacy of DFU healing using this method is still inadequate.However,in recent years,several MSCs-based drug delivery systems have emerged,which have shown to increase the efficacy of MSC therapy,especially in treating DFU.This review summarized the application of diverse MSCs-based drug delivery systems in treating DFU and suggested potential prospects for the future research.

Recent progress of respiratory inhalation drug delivery systems

With the influence of many factors such as the aging of the population,the younger smokers,and the serious air pollution,the incidence of chronic respiratory diseases is increasing year by year.In the treatment of respiratory diseases,clinical intervention is still mainly based on drug control of pulmonary symptoms.However,systemic drugs have disadvantages such as many adverse reactions and severe systemic side effects.In recent years,the research and development of local drug delivery systems for the respiratory tract has brought new changes to the treatment of respiratory diseases.Locally delivered drugs can directly act on the airways and have the characteristics of fast onset,good curative effect and small side effects.It is a simple,efficient and safe treatment method,which has a very significant effect,and has become a hot topic of current research and promotion.This paper briefly reviews the development track and latest research progress of respiratory local drug delivery systems at home and abroad,in order to provide reference for clinical workers in drug selection and application.

Charcoal Nanoparticles as a Delivery System for Doxorubicin and Sorafenib in Treatment of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditional chemotherapy drugs do not achieve satisfactory therapeutic efficacy. The delivery of therapeutic compounds to the target site is a major challenge in the treatment of many diseases. Objective: This study aims to evaluate activated charcoal nanoparticles as a drug delivery system for anticancer agents (Sorafenib and Doxorubicin) in Hepatocellular Cancer Stem Cells. Method: The percent efficiency of entrapment (% EE) of the doxorubicin and sorafenib entrapped onto the activated charcoal was obtained by determining the free doxorubicin and sorafenib concentration in the supernatant-prepared solutions. Then the characterizations of nanoparticles were formed by determination of the particle size distribution, zeta potential, and polydispersity index (PDI). The anticancer activity of activated Charcoal, Doxorubicin-ACNP, sorafenib-ACNP, free doxorubicin, and free sorafenib solutions was measured based on cell viability percentage in HepG2 cell lines (ATCC-CCL 75). In vitro RBC’s toxicity of Doxorubicin/sorafenib loaded charcoal was estimated by hemolysis percentage. Results: The synthesized Doxorubicin-ACNP and Sorafenib-ACNP were evaluated and their physiochemical properties were also examined. Essentially, the percent Efficiency of Entrapment (EE %) was found to be 87.5% and 82.66% for Doxorubicin-ACNP and Sorafenib-ACNP, respectively. The loading capacity was 34.78% and 24.31% for Doxorubicin-ACNP and Sorafenib-ACNP. Using the Dynamic Light scattering [DLS] for the determination of the hydrodynamic size and surface zeta potential, a narrow sample size distribution was obtained of (18, 68, and 190 nm for charcoal, 105, 255, and 712 nm for doxorubicin, and 91, 295, and 955 nm for sorafenib), respectively. A surface charge of −13.2, −15.6 and −17 was obtained for charcoal, doxorubicin/charcoal, and sorafenib/charcoal nanoparticles. The cytotoxic activity of Doxorubicin-ACNP and Sorafenib-ACNP was evaluated in-vitro against HepG2 cell lines and it was observed that Drug loaded ACNP improved anticancer activity when compared to Doxorubicin or Sorafenib alone. Moreover, testing the toxicity potential of DOX-ACNP and Sorafenib-ACNP showed a significant reduction in the hemolysis of red blood cells when compared to Doxorubicin and Sorafenib alone. Conclusion: In conclusion, it is notable to state that this study is regarded as the first to investigate the use of Activated charcoal for the loading of Doxorubicin and Sorafenib for further use in the arena of hepatocellular carcinoma. Doxorubicin-ACNP and Sorafenib-ACNP showed noteworthy anticancer activity along with a reduced potential of RBCs hemolysis rendering it as an efficacious carrier with a low toxicity potential.

A review on phospholipids and their main applications in drug delivery systems

Phospholipids have the characteristics of excellent biocompatibility and a especial amphiphilicity.These unique properties make phospholipids most appropriate to be employed as important pharmaceutical excipients and they have a very wide range of applications in drug delivery systems.The aim of this review is to summarize phospholipids and some of their related applications in drug delivery systems,and highlight the relationship between the properties and applications,and the effect of the species of phospholipids on the efficiency of drug delivery.We refer to some relevant literatures,starting from the structures,main sources and properties of phospholipids to introduce their applications in drug delivery systems.The present article focuses on introducing five types of carriers based on phospholipids,including liposomes,intravenous lipid emulsions,micelles,drug-phospholipids complexes and cochleates.

pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment

In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles （MSNs） with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanopartides, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail.

Electrospun nanofiber-based drug delivery systems

Electrospinning is a very simple and versatile process by which polymer nanofibers with di-ameters ranging from a few nanometers to sev-eral micrometers can be produced using an electrostatically driven jet of polymer solution or polymer melt. Significant progress has been made in this process throughout the past few years and electrospinning has advanced its ap-plications in many fields, including pharmaceu-tics. Electrospun nanofibers show great prom-ise for developing many types of novel drug delivery systems (DDS) due to their special characteristics and the simple but useful and effective top-down fabricating process. The current state of electrospun nanofiber-based DDS is focused on drug-loaded nanofiber preparation from pharmaceutical and biode-gradable polymers and different types of DDS. However, there are more opportunities to be exploited from the electrospinning process and the corresponding drug-loaded nanofibers for drug delivery. Additionally, some other related challenges and the possible resolutions are outlined in this review.

From oral formulations to drug-eluting implants:using 3D and 4D printing to develop drug delivery systems and personalized medicine

Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.

Transdermal drug delivery systems in diabetes management: A review

Diabetes mellitus is a chronic disease in which there is an insufficient production of insulin by the pancreas, or the insulin produced is unable to be utilized effectively by the body. Diabetes affects more than 415 million people globally and is estimated to strike about 642 million people in 2040. The WHO reported that diabetes will become the seventh biggest cause of mortality in 2030. Insulin injection and oral hypoglycemic agents remain the primary treatments in diabetes management. These often present with poor patient compliance. However, over the last decade, transdermal systems in diabetes management have gained increasing attention and emerged as a potential hope in diabetes management owing to the advantages that they offer as compared to invasive injection and oral dosage forms. This review presents the recent advances and developments in transdermal research to achieve better diabetes management. Different technologies and approaches have been explored and applied to the transdermal systems to optimize diabetes management. Studies have shown that these transdermal systems demonstrate higher bioavailability compared to oral administration due to the avoidance of first-pass hepatic metabolism and a sustained drug release pattern. Besides that, transdermal systems have the advantage of reducing dosing frequency as drugs are released at a predetermined rate and control blood glucose level over a prolonged time, contributing to better patient compliance. In summary, the transdermal system is a field worth exploring due to its significant advantages over oral route in administration of antidiabetic drugs and biosensing of blood glucose level to ensure better clinical outcomes in diabetes management.

Novel drug delivery systems for inflammatory bowel disease

Inflammatory bowel disease(IBD)is a chronic illness characterized by relapsing inflammation of the intestines.The disorder is stratified according to the severity and is marked by its two main phenotypical representations:Ulcerative colitis and Crohn’s disease.Pathogenesis of the disease is ambiguous and is expected to have interactivity between genetic disposition,environmental factors such as bacterial agents,and dysregulated immune response.Treatment for IBD aims to reduce symptom extent and severity and halt disease progression.The mainstay drugs have been 5-aminosalicylates(5-ASAs),corticosteroids,and immunosuppressive agents.Parenteral,oral and rectal routes are the conventional methods of drug delivery,and among all,oral administration is most widely adopted.However,problems of systematic drug reactions and low specificity in delivering drugs to the inflamed sites have emerged with these regular routes of delivery.Novel drug delivery systems have been introduced to overcome several therapeutic obstacles and for localized drug delivery to target tissues.Enteric-coated microneedle pills,various nano-drug delivery techniques,prodrug systems,lipid-based vesicular systems,hybrid drug delivery systems,and biologic drug delivery systems constitute some of these novel methods.Microneedles are painless,they dislodge their content at the affected site,and their release can be prolonged.Recombinant bacteria such as genetically engineered Lactococcus Lactis and eukaryotic cells,including GM immune cells and red blood cells as nanoparticle carriers,can be plausible delivery methods when evaluating biologic systems.Nano-particle drug delivery systems consisting of various techniques are also employed as nanoparticles can penetrate through inflamed regions and adhere to the thick mucus of the diseased site.Prodrug systems such as 5-ASAs formulations or their derivatives are effective in reducing colonic damage.Liposomes can be modified with both hydrophilic and lipophilic particles and act as lipid-based vesicular systems,while hybrid drug delivery systems containing an internal nanoparticle section for loading drugs are potential routes too.Leukosomes are also considered as possible carrier systems,and results from mouse models have revealed that they control anti-and pro-inflammatory molecules.

Camptothecin-based nanodrug delivery systems

The drug camptothecin has a wide range of antitumor effects in cancers including gastric cancer,rectal and colon cancer,liver cancer,and lung cancer.Camptothecin-based drugs inhibit topoisomerase 1(Topo 1),leading to destruction of DNA,and are currently being used as important chemotherapeutic agents in clinical antitumor treatment.However,the main obstacle associated with cancer therapy is represented by systemic toxicity of conventional anticancer drugs and their low accumulation at the tumor site.In addition,low bioavailability,poor water solubility,and other shortcomings hinder their anticancer activity.Different from traditional pharmaceutical preparations,nanotechnology-dependent nanopharmaceutical preparations have become one of the main strategies for different countries worldwide to overcome drug development problems.In this review,we summarized the current hotspots and discussed a variety of camptothecin-based nanodrugs for cancer therapy.We hope that through this review,more efficient drug delivery systems could be designed with potential applications in clinical cancer therapy.

ROS-responsive drug delivery systems for biomedical applications

In the field of biomedicine, stimuli-responsive drug delivery systems(DDSs) have become increasingly popular due to their site-specific release ability in response to a certain physiological stimulus, which may result in both enhanced treatment outcome and reduced side effects. Reactive oxygen species(ROS) are the unavoidable consequence of cell oxidative metabolism. ROS play a crucial part in regulating biological and physiological processes,whereas excessive intracellular ROS usually lead to the oxidation stress which has implications in several typical diseases such as cancer, inflammation and atherosclerosis. Therefore,ROS-responsive DDSs have elicited widespread popularity for their promising applications in a series of biomedical research because the payload is only released in targeted cells or tissues that overproduce ROS. According to the design of ROS-responsive DDSs, the main release mechanisms of therapeutic agents can be ascribed to ROS-induced carrier solubility change, ROS-induced carrier cleavage or ROS-induced prodrug linker cleavage. This review summarized the latest development and novel design of ROS-responsive DDSs and discussed their design concepts and the applications in the biomedical field.

Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor^(■) RH40 using experimental design

The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil(Kolliphor ~? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80(LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides(40% to 75%), Kolliphor ~? RH40(5% to 55%), LPC(0 to 40%) and ethanol(0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor~? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor~? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor ~? RH40 as a reference for formulation developers.

Recent advances in particulate drug delivery systems: Oral, pulmonary, and ophthalmic administrations

Colloidal drug carriers such as liposomes,lipid emulsions,and polymeric nanoparticles have great potential to deliver drugs effectively.Preparation of nano-crystals of API has also received much attention to design dosage forms to complete effective drug delivery.A variety of investigations have been carried out toward the design of an optimal particulate system.

A Study on the Multi-Compartment Linear Circulation Pharmacokinetic Model for the Targeting Drug Delivery System

By analyzing the observed phenomena and the data collected in the study, a multi-compartment linear circulation model for targeting drug delivery system was developed and the function formulas of the drug concentration-time in blood and target organ by computing were figured out. The drug concentration-time curve for target organ can be plotted with reference to the data of drug concentration in blood according to the model. The pharmacokinetic parameters of the drug in target organ could also be obtained. The practicability of the model was further checked by the curves of drug concentration-time in blood and target organ(liver) of liver-targeting nanoparticles in animal tests. Based on the liver drug concentration-time curves calculated by the function formula of the drug in target organ, the pharmacokinetic behavior of the drug in target organ(liver) was analyzed by statistical moment, and its pharmacokinetic parameters in liver were obtained. It is suggested that the (relative targeting index( can be used for quantitative evaluation of the targeting drug delivery systems.

An infection-microenvironment-targeted and responsive peptide-drug nanosystem for sepsis emergency by suppressing infection and inflammation

Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation.Nevertheless,current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens.Omiganan,an antimicrobial peptide,has shown promise for neutralizing endotoxins and eliminating diverse pathogens.However,its clinical application is hindered by safety and stability concerns.Herein,we present a nanoscale drug delivery system(Omi-hyd-Dex@HA NPs)that selectively targets infectious microenvironments(IMEs)and responds to specific stimuli for efficient intervention in sepsis.The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid(HA).The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes,but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase.The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation.In multiple tissue infection and sepsis animal models,Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction,thereby preventing subsequent fatal complications and significantly improving survival outcomes.The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.

Inhibitive Effect of Cremophor RH40 or Tween 80-based Self-microemulsiflying Drug Delivery System on Cytochrome P450 3A Enzymes in Murine Hepatocytes

This study examined the effect of self-microemulsiflying drug delivery system (SMEDDS) containing Cremophor RH40 or Tween 80 at various dilutions on cytochrome P450 3A (CYP3A) enzymes in rat hepatocytes, with midazolam serving as a CYP3A substrate.The particle size and zeta potential of microemulsions were evaluated upon dilution with aqueous medium.In vitro release was detected by a dialysis method in reverse.The effects of SMEDDS at different dilutions and surfactants at different concentrations on the metabolism of MDZ were investigated in murine hepatocytes.The cytotoxicity of SMEDDS at different dilutions was measured by LDH release and MTT technique.The effects of SMEDDS on the CYP3A enzymes activity were determined by Western blotting.Our results showed that dilution had less effect on the particle size and zeta potential in the range from 1:25 to 1:500.The MDZ was completely released in 10 h.A significant decrease in the formation of 1’-OH-MDZ in rat hepatocytes was observed after treatment with both SMEDDS at dilutions ranging from 1:50 to 1:250 and Cremophor RH 40 or Tween 80 at concentrations ranging from 0.1% to 1% (w/v), with no cytotoxicity observed.A significant decrease in CYP3A protein expression was observed in cells by Western blotting in the presence of either Cremophor RH40 or Tween 80-based SMEDDS at the dilutions ranging from 1:50 to 1:250.This study suggested that the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates.

Poly(NIPAM-co-MPS)-grafted multimodal porous silica nanoparticles as reverse thermoresponsive drug delivery system

Hybrid drug delivery systems(DDS) have been prepared by grafting poly(NIPAM-co-MPS) chains on multimodal porous silica nanoparticles having an inner mesoporous structure and an outer thin layer of micropores. The hybrid thermoresponsive DDS were fully characterized and loaded with a model drug. The in vitro drug release tests are carried out at below and above the lower critical solution temperature(LCST) of the copolymer. The results have revealed that due to the presence of small diameter(~1.3 nm) micropores at the periphery of the particles, the collapsed globules of the thermoresponsive copolymer above its LCST hinders the complete release of the drug which resulted in a reverse thermoresponsive drug release profile by the hybrid DDS.